Bendamustine hydrochloride, 4-{5-[bis(2-chloroethyl)amino]-1-methyl-2-benzimidazolyl}butyric acid hydrochloride salt:
was initially synthesized in 1963 in the German Democratic Republic (GDR) and was available from 1971 to 1992 there under the tradename Cytostasan®. Since that time, it has been marketed in Germany under the tradename Ribomustin®. Bendamustine hydrochloride is currently available in the United States under the tradename Treanda®(Cephalon, Inc., Frazer, Pa.). Bendamustine is an alkylating agent that has been shown to have therapeutic utility in treating diseases such as chronic lymphocytic leukemia, Hodgkin's disease, non-Hodgkin's lymphoma, multiple myeloma, and breast cancer.
The current commercial preparation of bendamustine hydrochloride entails at least nine synthetic steps, involving the use of several hazardous, odiferous reagents, such as thionyl chloride. See, for example, J. Prakt. Chem. 20, 178-186 (1963) and Zentralblatt fuer Pharmazie, Pharmakotherapie und Laboratoriumsdiagnostik 110 (10), 1013-1019 (1971). Despite its longstanding use in Germany, there have been very few attempts to modify the synthesis of bendamustine in order to reduce the number of synthetic steps and personnel exposure to hazardous reagents. As such, a need exists for a new synthesis of bendamustine that requires fewer synthetic steps and employs fewer hazardous reagents.